With more than 33 million people currently infected with human immunodeficiency virus (HIV) and 2 million additional individuals infected each year, there is a worldwide imperative to reduce transmission of this deadly virus. Worldwide, sexual transmission is the primary route of new virus infections. Strategies to reduce spread of this virus can be achieved by reducing virus loads in currently infected individuals (and thereby reducing levels of virus exposure) and/or by blocking sexual transmission by the use of effective and safe microbicides.
Clinically useful anti-retrovirals target a number of steps of the HIV-1 life cycle including co-receptor (CCR5) binding, virus membrane/cellular membrane fusion, reverse transcription, integration and proteolytic processing. See, e.g., Martins et al., Curr. Med. Chem., 15, 1083 (2008). Combination therapy regiments have proved highly efficacious at controlling HIV-1 load in most infected individuals. Nonetheless, drug resistant HIV-1s arise and are transmitted between individuals, reducing the efficacy of currently available antivirals. See, e.g., A. M. Wensing et al., Antiviral Res., 85, 59 (2010); S. Broder. Antiviral. Res., 85, 1 (2010); and J. A. Este et al., Antiviral Res., 85, 25(2010). Additionally, some of the HIV antivirals have significant off target effects that result in cytotoxicity, and many of these antivirals are expensive, thereby decreasing their attractiveness as daily use microbicides through the world and limiting their use as antivirals in developing countries. There remains a need for additional non-toxic HIV microbicides as well as antiviral therapies that can be broadly and safely used.
The mint family (Lamiaceae) produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L.), sage (Salvia spp.), peppermint (Mentha×piperita L.), hyssop (Hyssopus officinalis L.), basil (Ocimum spp.) and self-heal (Prunella vulgaris L.).
The mint (Lamiaceae) family member, Prunella vulgaris, or “self-heal” has been evaluated by the Iowa Center for Botanical Dietary Supplements for anti-HIV activity. Water- and ethanol-based extracts were tested for their ability to inhibit HIV-1 infection. Aqueous extracts displayed potent anti-retroviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in virus/cell interaction studies, extracts effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that the extracts were most effective at targeting post-binding entry events. See, C. Oh et al., Virology J., 8, 188 (2011).
However, the structures of the compounds responsible for this bioactivity have not been determined. Therefore, a continuing need exists for purified, well-characterized compounds with potent anti-HIV activity and good therapeutic indices. Antivirals targeting early steps within the HIV life cycle such as receptor binding or fusion events may be particularly attractive HIV inhibitors since these agents block the initiation of the infectious cycle, thereby preventing virus entry into the host cell.